Gene Therapy for Phenylketonuria

Not currently recruiting at 28 trial locations

Overseen By Trial Transparency email recommended (Toll free for US & Canada)

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Sanofi

Disqualifiers: Liver disease, HIV, Hepatitis B, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 41

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy treatment called SAR444836 for individuals with phenylketonuria (PKU), a condition where the body cannot break down the amino acid phenylalanine (Phe). The goal is to determine if this treatment can safely lower Phe levels in the blood and eliminate the need for a strict Phe-restricted diet. Participants will receive a one-time IV dose, and the trial will monitor the treatment's effectiveness and any side effects. It suits adults with PKU who struggle to manage their condition despite following a special diet. As a Phase 1/Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to be among the first to benefit from this innovative therapy.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you must maintain your current diet unless directed otherwise by the study protocol.

Is there any evidence suggesting that SAR444836 is likely to be safe for humans?

Research has shown that the gene therapy treatment SAR444836 has generally been well-tolerated in studies so far. Some patients experienced temporary increases in liver enzymes, proteins that help the liver function properly, but these changes did not persist. This indicates the treatment did not cause lasting harm.

While researchers continue to gather information on long-term safety, early results are promising. It's important to remember that this therapy remains under testing, so researchers are closely monitoring for any possible side effects. Overall, current findings are positive regarding the safety of SAR444836 for people with phenylketonuria (PKU). ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for phenylketonuria (PKU), which often involve strict dietary management and supplementation with amino acid formulas, SAR444836 offers a groundbreaking approach through gene therapy. This treatment introduces a functional copy of the gene responsible for breaking down phenylalanine, aiming to correct the underlying genetic issue rather than just managing symptoms. Researchers are excited because this method has the potential to provide a long-term solution, reducing or even eliminating the need for lifelong dietary restrictions and supplements.

What evidence suggests that this gene therapy could be an effective treatment for phenylketonuria?

Research shows that SAR444836, a type of gene therapy studied in this trial, aims to provide a long-term solution for phenylketonuria (PKU). It delivers a healthy version of the PAH gene into liver cells. This gene helps break down phenylalanine (Phe), an amino acid that accumulates in people with PKU. Early studies of similar gene therapies have shown promise in lowering Phe levels and allowing a more normal diet. Preclinical results have been encouraging, demonstrating effective gene delivery and Phe reduction. Although human data is still emerging, these findings suggest that SAR444836 could be a promising option for managing PKU. ^{2 3 6 7 8}

Who Is on the Research Team?

Clinical Sciences & Operations

Principal Investigator

Sanofi

Are You a Good Fit for This Trial?

Adults aged 18-65 with Phenylketonuria (PKU) due to PAH deficiency, who have been on a stable diet restricting phenylalanine. Participants must have had high plasma Phe levels in the past while on this diet and be willing to maintain their current diet for the trial's duration. They should not be able to bear children, have a BMI ≤ 35 kg/m2, and agree to use contraception.

Inclusion Criteria

My blood tests show high phenylalanine levels twice, despite my diet.

My blood Phe levels were high twice in the last year despite my special diet.

Body mass index (BMI) ≤ 35 kg/m2

Exclusion Criteria

Presence of neutralizing antibodies against the AAV SNY001 capsid

I do not have HIV, active hepatitis B or C, or any serious infection.

Abnormal liver function laboratory testing evidenced by alanine aminotransferase (ALT)>1.5X upper limit normal (ULN), aspartate transaminase (AST)>1.5X ULN, alkaline phosphatase >1.5X ULN, Total and direct bilirubin >1.5X ULN (bilirubin levels above the laboratory's normal range are acceptable in individuals with a documented history or laboratory evidence of Gilbert's Disease)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

6 weeks

Treatment

Participants receive a one-time intravenous administration of SAR444836

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including clinical and laboratory assessments to evaluate the effect of SAR444836 on blood Phe levels

96 weeks

40 visits (remote and in-person)

What Are the Treatments Tested in This Trial?

Interventions

• SAR444836

Trial Overview

The study tests SAR444836, a gene therapy aiming to treat PKU by introducing a functional version of the PAH enzyme via an adeno-associated virus vector. It involves one IV administration followed by monitoring over approximately two years with up to 41 visits which may include remote assessments.

How Is the Trial Designed?

Group I: SAR444836 Experimental Treatment 1 Intervention

Participants will receive a single dose of SAR444836 on Day 1

Who Is Running the Clinical Trial?

Sanofi

Lead Sponsor

Trials

2,246

Recruited

4,085,000+

Paul Hudson

Sanofi

Chief Executive Officer since 2019

Degree in Economics from Manchester Metropolitan University

Christopher Corsico

Sanofi

Chief Medical Officer

MD from Cornell University, MPH in Chronic Disease Epidemiology from Yale University

Published Research Related to This Trial

A gene therapy using a recombinant adeno-associated virus (rAAV) vector successfully normalized blood phenylalanine levels in a PKU mouse model, demonstrating significant long-term efficacy without toxicity or immune response.

This approach achieved complete correction of hyperphenylalaninemia in both male and female mice, suggesting that a single intravenous injection could be a promising future treatment for PKU patients, overcoming limitations of current dietary restrictions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Administration-route and gender-independent long-term therapeutic correction of phenylketonuria (PKU) in a mouse model by recombinant adeno-associated virus 8 pseudotyped vector-mediated gene transfer. Ding, Z., Georgiev, P., Thöny, B.[2013]

Gene therapy using adeno-associated viruses (AAVs) to deliver the phenylalanine hydroxylase (PAH) enzyme has shown effective and sustained clearance of phenylalanine (Phe) in mice for over a year, indicating a potential long-term treatment for phenylketonuria (PKU).

Combining PAH gene therapy with supplementation or gene therapy for tetrahydrobiopterin (BH(4)) in skeletal muscle resulted in significant and lasting reductions in blood Phe levels, suggesting a dual approach could be a viable alternative to the strict dietary restrictions currently required for PKU patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term correction of murine phenylketonuria by viral gene transfer: liver versus muscle. Thöny, B.[2021]

The study demonstrated that using a synthetic AAV vector (Anc80) to deliver a functional copy of the PAH gene in a mouse model of PKU resulted in a significant and lasting reduction of phenylalanine levels, indicating effective restoration of metabolic function.

Administration of the AAV vector was safe, with no serious adverse effects observed even at the highest tested dose, and only minor, transient changes in liver enzymes, suggesting a promising approach for gene therapy in PKU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model. Kaiser, RA., Weber, ND., Trigueros-Motos, L., et al.[2022]

AAV8-PAL gene therapy effectively corrected high phenylalanine levels in both male and female PKU mice, demonstrating long-term efficacy after a single intravenous treatment.

The therapy showed no significant liver injury, indicating a safe approach for potential treatment of phenylketonuria (PKU) in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Metabolic Correction of Phenylketonuria by AAV-Delivered Phenylalanine Amino Lyase. Tao, R., Xiao, L., Zhou, L., et al.[2022]

In female PKU mice, the administration of mPAH cDNA using a phiBT1 bacteriophage integration system completely corrected the hyperphenylalaninemic and hypopigmentation phenotypes after 10 weekly treatments, demonstrating the efficacy of this gene therapy approach.

The study found no liver pathology in the mice even after multiple administrations, indicating that this method is safe for repeated use in gene therapy for metabolic disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correction in female PKU mice by repeated administration of mPAH cDNA using phiBT1 integration system. Chen, L., Woo, SL.[2017]

In a study using the Pah(enu2/enu2) PKU mouse model, an oral enzyme substitution therapy with a modified phenylalanine ammonia lyase (PAL) significantly reduced plasma phenylalanine levels by approximately 40%, demonstrating its efficacy (p=0.0029).

The reduction in phenylalanine was dose- and loading-dependent, suggesting that more frequent and smaller doses could enhance treatment effectiveness, making oral PAL therapy a promising adjunct to dietary management for patients with phenylketonuria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of orally administered PEGylated phenylalanine ammonia lyase in mice for the treatment of Phenylketonuria. Sarkissian, CN., Kang, TS., Gámez, A., et al.[2022]

Recombinant phenylalanine ammonia-lyase (PAL) from parsley, when chemically modified with PEG, showed improved stability in circulation and effectively reduced plasma phenylalanine levels in mice, suggesting its potential as a treatment for phenylketonuria (PKU).

This approach addresses the challenges of low stability and antigenicity associated with plant-derived enzymes, making PEG-PAL a promising therapeutic option for individuals with PKU who need to manage elevated phenylalanine levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phenylalanine ammonia-lyase modified with polyethylene glycol: potential therapeutic agent for phenylketonuria. Ikeda, K., Schiltz, E., Fujii, T., et al.[2018]

Long-term enzyme substitution therapy in adults with phenylketonuria (PKU) has shown unexpected improvements in neuropsychiatric outcomes, suggesting a potential shift in treatment perspectives for this condition.

Various gene therapy approaches, including rAAV vectors and genome editing, have successfully targeted the liver in mouse models of PKU, indicating promising avenues for future human gene therapy applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

State-of-the-Art 2019 on Gene Therapy for Phenylketonuria. Grisch-Chan, HM., Schwank, G., Harding, CO., et al.[2023]

Gene therapy using a recombinant AAV2/8 vector successfully restored phenylalanine hydroxylase (PAH) activity in female PKU mice, achieving 65-70% of normal levels, which is a significant improvement over previous treatments that only worked in males.

The treatment not only normalized plasma phenylalanine levels in female PKU mice but also protected their offspring from the harmful effects of maternal PKU syndrome, suggesting a promising therapeutic approach for managing PKU in females.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protective effect of recombinant adeno-associated virus 2/8-mediated gene therapy from the maternal hyperphenylalaninemia in offsprings of a mouse model of phenylketonuria. Jung, SC., Park, JW., Oh, HJ., et al.[2018]

Citations

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congress.sanofimedical.com

congress.sanofimedical.com/s3fs-public/2024-08/Phase%2012%20open%20label%20study%20design%20to%20evaluate%20safety%2C%20tolerability%2C%20and%20efficacy%20of%20SAR444836%2C%20an%20AAV%20mediated%20gene%20transfer%20in%20patients%20with%20phenylketonuria.pdf?VersionId=yo514ZRuJvJQKkvphl_qhOebUX812Ql3

Phase 1/2 open-label study design to evaluate safety ...

SAR444836, an AAV vector-mediated gene transfer of human. PAH, is designed to deliver a functional copy of the human PAH gene into hepatocytes using a one-time ...

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12428815/

Advancing Gene Therapy for Phenylketonuria

This review details the pathophysiology of PKU treatment, and progress in preclinical and clinical gene therapy strategies. Emphasis is on ...

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clinicaltrialsarena.com

clinicaltrialsarena.com/news/biomarins-trial-phenylketonuria/

BioMarin's trial for PKU therapy meets primary efficacy ...

BioMarin has reported that the multi-centre Phase III PEGASUS trial of Palynziq (pegvaliase-pqpz) has met its primary efficacy endpoint.

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scge.mcw.edu

scge.mcw.edu/platform/data/clinicalTrials/report/NCT05972629

Gene Therapy Trial Report

A Phase 1/Phase 2 Open-label Study to Evaluate the Safety, Tolerability, and Efficacy of a Single Intravenous Administration of SAR444836 in Adult Participants

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clinicaltrials.gov

clinicaltrials.gov/study/NCT03952156?cond=%22Phenylketonurias%22&viewType=Table&rank=2

Gene Therapy Clinical Study in Adult PKU (pheNIX)

Part 1 of this study will evaluate the safety and efficacy of HMI-102 gene therapy in adult subjects with PKU due to PAH deficiency. Subjects will receive a ...

6.

sanofistudies.com

sanofistudies.com/cwout/CW-V9DEXS//us/en/listing/312855/a-phase-1phase-2/

Gene Therapy Study for Phenylketonuria

This study investigates the use of an investigational gene therapy for adults with phenylketonuria (PKU), a condition where the body cannot ...

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC6763965/

State-of-the-Art 2019 on Gene Therapy for Phenylketonuria

In this article we summarize the gene therapeutic attempts of correcting a mouse model for PKU and discuss the future implications for human gene therapy.

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biomarin.com

biomarin.com/news/press-releases/u-s-fda-placed-a-clinical-hold-on-bmn-307-phearless-phase-1-2-gene-therapy-study-in-adults-with-pku-based-on-interim-pre-clinical-study-findings/

U.S. FDA Placed a Clinical Hold on BMN 307 Phearless ...

The Phearless study is evaluating BMN 307, an investigational AAV5-phenylalanine hydroxylase (PAH) gene therapy, in adults with phenylketonuria (PKU).